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Available data suggest that sex hormone levels during puberty may affect symptom onset and expression, treatment responsiveness and outcomes in schizophrenia, whereas post-pubertal adolescents may have a similar clinical presentation and treatment response compared to adults with schizophrenia.
Post-hoc analyses were conducted to assess the similarity of short- and long-term efficacy between post-pubertal adolescents and adults with schizophrenia treated with aripiprazole.
Based on available European epidemiologic data, a cut-off age of 15 years was used to isolate a subgroup of mostly post-pubertal adolescents with schizophrenia in aripiprazole clinical studies. Outcome measures from this subgroup (ages 15-17; n=147) were then compared to outcomes from one adult study (n=853) on short and long-term measures of efficacy, including PANSS scores, response rates, and remission rates.
Comparable short and long-term treatment effects were observed on the PANSS total and subscale scores, demonstrated by overlapping 95% confidence intervals (mean change from baseline in PANSS total score (OC dataset): at week 6 in adults: -27,7; in adolescents 15-17 yr: -29,6; at week 30 in adults: -39,2; in adolescents 15-17 yr: -36). Percent of adolescents achieving response (defined as ≥ 30% decrease in PANSS total score from baseline) at 32 weeks (80,2%) on open label treatment was similar to that in adult studies at week 34 (80%) on double blind treatment (OC dataset).
Adolescents with schizophrenia (ages 15-17, mostly post-pubertal) demonstrate a positive treatment response in short-term and long-term studies which is similar to that observed in the adult patient population.
To compare the efficacy of aripiprazole and haloperidol for the treatment of acute relapse in chronic schizophrenia.
Across two 52-week double-blind studies, 1294 patients with acute relapse of chronic schizophrenia were randomized to aripiprazole 30 mg/day (n=861) or haloperidol 10 mg/day (n=433). The mean change in (Positive and Negative Syndrome Scale) PANSS Total score, PANSS Positive score were secondary endpoints in both studies. Post-hoc, a measure of excitement and hostility was derived from PANSS score items by factor analysis. The scales were administered at baseline and at each double-blind study visit (Weeks 1-8, 10, 12, 14, then every 4 weeks to Week 52).
Aripiprazole produced similar improvements to haloperidol in PANSS Total score (last observation carried forward, LOCF). Among those patients who completed the study, aripiprazole showed a significantly greater improvement in PANSS Total score compared with haloperidol at Weeks 26 and 52. A similar improvement in PANSS Positive score was seen with aripiprazole and haloperidol (LOCF and observed cases [OC]). Symptoms of excitement and hostility also improved similarly with both agents throughout the study (LOCF and OC).
Aripiprazole showed similar efficacy to haloperidol over the 52-week study, and significantly greater efficacy among those patients who stayed on treatment. Thus, aripiprazole is a useful agent for long-term maintenance therapy in schizophrenia.
The primary objective of this FDA-requested study was to examine the tolerability, safety, and pharmacokinetics (PK) of 20, 25, and 30 mg/day of aripiprazole in children and adolescents, ages 10-17.
21 patients were enrolled in this open-label, sequential cohort trial that employed a forced escalation paradigm. A 2 mg starting dose was increased to 5, 10, 15, 20, 25, or 30 mg (depending on the final dose) in 2-day, stepwise intervals. After this initial dose-escalation phase, subjects were maintained at their target dose for an additional 14 days. Study medication was given once daily. Preferential enrollment was given to patients with schizophrenia or bipolar illness. Blood samples were collected for aripiprazole concentrations.
Using the described dose-escalation schedule, all 3 dose levels were well tolerated, in general. One subject discontinued treatment due to acute, moderate dystonia. Other adverse events were in the mild/moderate range and were transient in nature. Aripiprazole pharmacokinetics are linear across doses and similar to that observed in adult patients.
• Doses of 20, 25 and 30 mg/day (following titration from a starting dose of 2 mg) are generally well tolerated in children and adolescents without regard to gender or psychiatric diagnosis.
• Aripiprazole pharmacokinetics are linear in child and adolescent patients.
The primary objective of this FDA-requested study was to examine the tolerability/safety and pharmacokinetics (PK) of 20 mg, 25 mg, and 30 mg per day of aripiprazole in children and adolescents, ages 10-17. Effectiveness of aripiprazole was also assessed in this patient population, and is described as the focus of this poster.
This was an open-label, 26-day, multi-center, sequential cohort, dose-escalation trial. Twenty-one (21) children and adolescents, aged 10 to 17 years old, were enrolled. Preferential enrollment was given to patients with schizophrenia or bipolar illness; however, other psychiatric diagnoses were also permitted. Fifty-seven percent (57%) of patients were diagnosed with bipolar disorder; 24%, Tourette's disorder; and 5%, schizophrenia, PDD, OCD, or conduct disorder. Patients started on a dose of aripiprazole 2 mg/day. Three cohorts reached final doses of 20, 25, or 30 mg/day over a maximum of 12 days and maintained that dose for an additional 14 days. Effectiveness was assessed using the CGI-Severity and CGI-Improvement scales.
Eighty-five percent (17/20) of the patients were “much improved” or “very much improved” at study endpoint (CGI-I).
• Effectiveness of aripiprazole at doses of 20-30 mg/day is demonstrated in this child and adolescent patient population
• Observation of clinically meaningful improvement of global symptoms supports systematic evaluation in pediatric/adolescent disorders
Optimal management of schizophrenia in adolescents is limited by the lack of available therapies. The efficacy and tolerability of aripiprazole was investigated in this patient population.
This 6-week, randomized, double-blind, placebo controlled trial was conducted at 101 international centers, with a safety monitoring board. 13-17 year-olds with a DSM-IV diagnosis of schizophrenia were randomized to placebo, or a fixed dose of aripiprazole 10 mg or 30 mg reached after a 5 or 11 day titration, respectively. The primary endpoint was mean change from baseline on the PANSS Total score at week 6. Secondary endpoints included the PANSS Positive and Negative subscales, and CGI Improvement score. Tolerabilility assessements included frequency and severity of adverse events, as well as blood chemistries, metabolic parameters and weight gain.
Over 85% of 302 patients completed this study. Both 10 mg and 30 mg doses were superior to placebo on the primary endpoint (PANSS total), with significant differences observed as early as Week 1 (30mg). Both doses showed significant improvement on the PANSS Positive and CGI-I scales; and the 10 mg dose group was superior on PANSS Negative score. Approximately 5% of aripiprazole patients discontinued due to AEs. Weight gain and changes in prolactin were minimal.
10mg and 30mg doses of aripiprazole were superior to placebo in the treatment of adolescents with schizophrenia. Aripiprazole was well tolerated, in general, with few discontinuations due to AEs. EPS was the most common AE. Change in body weight was similar to placebo.
There is limited published data from long-term pediatric bipolar clinical trials with which to guide appropriate treatment decisions. Long-term efficacy and safety of aripiprazole was investigated in this patient population.
296 youths, ages 10-17 year-old with a DSM-IV diagnosis of bipolar I disorder were randomized to receive either placebo or aripiprazole (10mg or 30mg) in a 4-week double-blind trial. Completers continued assigned treatments for an additional 26 weeks (double-blind). Efficacy endpoints included mean change from baseline to week 4 and week 30 on the Young Mania Rating Scale; Children's Global Assessment Scale, Clinical Global Impressions-Bipolar version severity scale, General Behavior Inventory, Attention Deficit Hyperactivity Disorders Rating Scale, and time to discontinuation. Tolerability/safety assessments included incidence and severity of AEs, blood chemistries and metabolic parameters.
Over the 30-week course of double-blind treatment, aripiprazole (10 mg and 30 mg) was superior to placebo as early as week 1 (p< 0.002) and at all scheduled visits from week 2 through week 30 on mean change from baseline in the Y-MRS total score (p<.0001; all visits). Significant improvements were observed on multiple endpoints including the CGAS, GBI, CGI-BP, ADHD-RS-IV total score, time to discontinuation, and response and remission rates. The 3 most common AEs were somnolence, extrapyramidal disorder, and fatigue. Mean change in body weight z-scores over 30 weeks was not clinically significant.
Over 30-weeks of treatment, both doses of aripiprazole were superior to placebo in the long term treatment of pediatric bipolar patients. Aripiprazole was generally well tolerated.
Evaluate the efficacy of aripiprazole combination with lithium/valproate vs. placebo combination in bipolar mania using a titration regimen with a low starting dose (5 mg/day).
Eligible adult patients with bipolar mania receiving lithium/valproate and a Young Mania Rating Scale (YMRS) Total score ≥16 who might benefit from combination treatment with aripiprazole, were randomized to aripiprazole (n=181) or placebo (n=189) with lithium/valproate. Primary endpoint was mean change from baseline to Week 12 in YMRS. Secondary endpoints were Clinical Global Impressions-Bipolar Version (CGI-BP) severity of illness score, response rate (≥50% improvement in YMRS Total score), and remission rate (YMRS ≤12). Safety and tolerability were also assessed. Enrolment yielded a 77% power to detect a 2.6-point change in YMRS Total score at endpoint.
At endpoint, the mean change in YMRS Total Score (last-observation-carried-forward [LOCF]) for aripiprazole vs. placebo was not significant (treatment difference [-2.04] in favour of aripiprazole (95% CI: -4.14, 0.07; p=0.058). Mean change from baseline to endpoint in CGI-BP showed a treatment difference (-0.30) in favour of aripiprazole vs. placebo (95% CI: - 0.59, -0.01; p=0.044). Response rates were 68.8% vs. 61.3% (p=0.128) and remission rates were 69.9% vs. 64.0% (p=0.211) for aripiprazole and placebo, respectively. No unexpected adverse events (AEs) occurred. Treatment-emergent AEs (≥5% and twice the rate of placebo) were akathisia, depression, and nausea.
The target sample size of 388 patients was not achieved in this study and the primary outcome did not reach statistical significance. Now new or unexpected AEs occurred.
Evaluate the efficacy and long-term safety of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.
Patients requiring chronic treatment for schizophrenia, not on aripiprazole monotherapy, were cross-titrated from other antipsychotic(s) to aripiprazole in an oral conversion phase (Phase 1). All patients entered an oral aripiprazole stabilization phase (Phase 2). Patients meeting stability criteria entered an ARI-OM stabilization phase (Phase 3), with coadministration of oral aripiprazole for the first 2 weeks. Patients meeting stability criteria were randomized to ARI-OM or placebo once-monthly (placebo-OM) during a 52-week, double-blind maintenance phase (Phase 4). Primary endpoint was time-to-impending relapse. Safety and tolerability were also assessed.
710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo-OM=134). The study was terminated early because efficacy was demonstrated by a pre-planned interim analysis. Time-to-impending relapse was significantly delayed with ARI-OM vs. placebo-OM (p< 0.0001, log-rank test). Discontinuations due to treatment-emergent adverse events (AEs) were: Phase 1, 3.8% (n=24/632); Phase 2, 3.0% (n=21/709); Phase 3, 4.9% (n=28/576); Phase 4, 7.1% (n=19/269). Most AEs were mild or moderate. Insomnia was the only AE >5% incidence in any phase. Headache, somnolence, and nausea had a peak first onset within the first 4 weeks of treatment. There were no unusual shifts in all phases in laboratory values, fasting metabolic parameters, weight, or objective scales of movement disorders.
ARI-OM significantly delayed time-to-impending relapse compared with placebo-OM and was well tolerated as maintenance treatment in schizophrenia1.
Evaluate the effectiveness of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.
Detailed methodology has been published previously1. Briefly, the study consisted of 4 phases: oral conversion to aripiprazole (Phase 1); oral aripiprazole stabilization (Phase 2); ARI-OM stabilization (Phase 3), with co-administration of oral aripiprazole for the first 2 weeks; and an ARI-OM maintenance phase (Phase 4). Effectiveness assessments included Investigator's Assessment Questionnaire (IAQ) scores, a scale that evaluates effectiveness of current treatment vs. pre-trial medication, where a negative change in score signals improvement, and Personal and Social Performance (PSP) scale scores, where negative change in score signals worsening.
710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo once-monthly [placebo- OM]=134). Mean IAQ Total scores remained stable in Phase 2 (31.3) and Phase 3 (30.6). During Phase 4, the mean change in IAQ Total score was +1.3 for ARI-OM vs. +3.8 for placebo-OM (p< 0.0001). Mean changes in PSP Total scale scores showed improvement during Phase 2 (3.0) and Phase 3 (2.6). Mean change in PSP scores during Phase 4 showed greater functional stability with ARI-OM (−1.7) compared with placebo-OM (−6.2) (p=0.0002 vs. placebo-OM).
Improvements in effectiveness, as assessed by the IAQ and PSP Total scale scores, in the Phases 2 & 3 were maintained in Phase 4 for ARI-OM compared with placebo-OM. Treatment with ARI-OM improved symptoms, overall response to treatment and functioning.
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